Epilepsy is a common and chronic disease which affects about 1% of the global population. Although a number of new antiepileptic drugs (AEDs) have been introduced recently in Europe and the U.S., at present there are only four major AEDs: phenobarbital, phenytoin, carbamazerpine and valproic acid. With the existing medications, about 25% of epileptic patients are still not seizure-free even if the therapy is optimally managed (R. H. Levy and D. D. Shen. in Levy R. H. et al (eds) Antiepileptic Drugs, 4th edition, Raven Press, N.Y. 1995 pp. 605-620 and other chapters on valproate therein). In addition, therapy with existing AEDs is associated with side effects which increase the morbidity of epileptic patients.
Antiepileptic drug therapy treats the symptoms (seizure) while the cause of the epilepsy in many cases remains unknown. Since AEDs have to be administered repetitively as chronic treatment in antiepileptic therapy, the issues of side effects and drug toxicity are cardinal. Therefore, efforts are on-going to develop new and potent AEDs with minimal side effects (Bialer M. et al Pharm. World Sci. 16: 2-6, 1994).
Valproic acid (VPA-I), one of the major antiepileptic drugs (AEDs) is associated with teragenecity and hepatotoxicity. So far, world wide 132 patients have died from VPA-associated liver failure or fatal hepatotoxicity. A strong association exists between maternal use of antiepileptic drugs (AEDs) during pregnancy and birth defects in offspring. The overall malformation rate is 11.1% in the offspring of untreated epileptic mothers and 4.8% in those of the general population. VPA treatment during pregnancy may result in a 5- to 10-fold increase in the incidence of neural tube defects compared with incidence in the general population. ##STR2##
The present invention provides a new CNS-active amide derivative of VPA, the compound 2-hydroxypropyl valpromide (HP-VPD), which is more potent as an antiepileptic than VPA.
As a chiral molecule with one asymmetric carbon racemic HP-VPD is a mixture of two enantiomers (R)-HP-VPD (II) and (S)-HP-VPD (III). Since HP-VPD is a chiral molecule its individual optical isomers may have different pharmacokinetics, pharmacodynamics potency and teratogenecity. ##STR3##
The two enantiomers of HP-VPD were prepared by a stereospecific synthesis and their antiepileptic activity and neurotoxicity was analyzed in comparison to racemic HP-VPD and VPA (I). Individual enantiomers and racemic HP-VPD were screened following oral administration to rats for their anticonvulsant activity and neuriotoxicity at the NIH Epilepsy Branch by the maximal electoshock (MES) test which measures seizure spread; by the subcutaneous metrazol (sc Met) test, which measures seizure threshold; and by the rotorod ataxia test, which assesses minimal neurotoxicity.
Anticonvulsant activity at the maximal electoshock (MES) test has been associated with antiepileptic activity in complex partial epilepsy which is common epilepsy among therapy-resistant (refractory) epileptic patients. The results of the study show that the (S)-HP-VDP in particular, has a potential to become a new efficient antiepileptic drug.
The fact that unlike VPA, different valproylamide analogue were found to be non-teratogenic in animal studies (H. Nau and A. G. Hendricks ISI Atlas Sci: Pharmacol. 1, 52-56, 1987 and M. Radatz et. al. Epilepsy Res. 20:41-49, 1998) give the HP-VPD the potential to be non-teratogenic entity.